Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells

J Clin Invest. 2021 Jul 15;131(14):e142116. doi: 10.1172/JCI142116.


Glioblastoma multiforme (GBM), the most aggressive brain cancer, recurs because glioblastoma stem cells (GSCs) are resistant to all standard therapies. We showed that GSCs, but not normal astrocytes, are sensitive to lysis by healthy allogeneic natural killer (NK) cells in vitro. Mass cytometry and single-cell RNA sequencing of primary tumor samples revealed that GBM tumor-infiltrating NK cells acquired an altered phenotype associated with impaired lytic function relative to matched peripheral blood NK cells from patients with GBM or healthy donors. We attributed this immune evasion tactic to direct cell-to-cell contact between GSCs and NK cells via αv integrin-mediated TGF-β activation. Treatment of GSC-engrafted mice with allogeneic NK cells in combination with inhibitors of integrin or TGF-β signaling or with TGFBR2 gene-edited allogeneic NK cells prevented GSC-induced NK cell dysfunction and tumor growth. These findings reveal an important mechanism of NK cell immune evasion by GSCs and suggest the αv integrin/TGF-β axis as a potentially useful therapeutic target in GBM.

Keywords: Brain cancer; Cancer immunotherapy; Immunology; NK cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Glioblastoma / genetics
  • Glioblastoma / immunology*
  • Glioblastoma / pathology
  • Glioblastoma / therapy
  • Heterografts
  • Humans
  • Integrins / genetics
  • Integrins / immunology*
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / pathology
  • Male
  • Mice
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology*
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / immunology*
  • Neoplastic Stem Cells / pathology
  • Receptor, Transforming Growth Factor-beta Type II / genetics
  • Receptor, Transforming Growth Factor-beta Type II / immunology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / immunology*


  • ITGA5 protein, human
  • Integrins
  • Neoplasm Proteins
  • Transforming Growth Factor beta
  • Receptor, Transforming Growth Factor-beta Type II
  • TGFBR2 protein, human